Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer
Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer
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DOI：
10.1016/j.lungcan.2009.02.004
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发表时间：
2009-11-01
期刊：
影响因子：
5.3
通讯作者：
Takahashi, Kazuhisa
中科院分区：
文献类型：
--
作者：
Gu, Tao;Ohashi, Rina;Takahashi, Kazuhisa
骨桥蛋白（OPN）是一种多功能细胞因子，参与细胞的存活、迁移和粘附，与肿瘤的发生、发展和转移有关。然而，OPN在人肺癌化疗敏感性中的作用尚未阐明。本研究旨在探讨骨桥蛋白在肺癌细胞化疗敏感性中的作用。我们从人小细胞肺癌细胞系SBC-3中开发了稳定的OPN转染子（SBC-3/OPN）和对照转染子（SBC-3/NEO）。SBC-3/OPN细胞对顺铂的耐药性高于SBC-3/NEO细胞。多药耐药相关蛋白（MRP）似乎不参与获得性耐药的发展，因为MRP抑制剂不改变化疗敏感性。与SBC-3/NEO细胞相比，暴露于顺铂后，凋亡的SBC-3/OPN细胞的数量减少。顺铂处理后，SBC-3/NEO细胞抗凋亡蛋白bcl-2的表达下调，而SBC-3/OPN细胞则无明显变化。与此相反，促凋亡蛋白bax在SBC-3/OPN和SBC-3/NEO细胞中没有改变，因此SBC-3/NEO细胞中bcl-2/bax比值降低，而SBC-3/OPN细胞中没有改变。SBC-3/NEO细胞中caspase-3和caspase-9的活化增强，但SBC-3/OPN细胞中caspase-3和caspase-9的活化不增强。我们的研究结果表明，OPN通过抑制bcl-2蛋白的下调，从而阻断caspase-9和caspase-3依赖的细胞凋亡，增强SBC-3细胞对顺铂的化疗耐药性。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Osteopontin (OPN) is a multi-functional cytokine involved in cell survival, migration and adhesion which is associated with tumorigenesis, progression and metastasis. However, the role of OPN in chemosensitivity of human lung cancer has not yet been elucidated. The purpose of this study is to investigate the role of OPN in chemo-sensitivity of lung cancer cells. We developed a stable OPN transfectant (SBC-3/OPN) and a control transfectant (SBC-3/NEO) from human small cell lung cancer cell line, SBC-3. SBC-3/OPN cells were more resistant to cisplatin than SBC-3/NEO cells. Multi-drug resistance-associated protein (MRP) does not appear to be involved in the development of acquired chemo-resistance, since MRP inhibitor did not alter chemo-sensitivity. After exposure to cisplatin, the apoptotic SBC-3/OPN cells were reduced in number compared to SBC-3/NEO cells. Treatment with cisplatin revealed that the expression of antiapoptotic protein, bcl-2, was down-regulated in SBC-3/NEO cells, while that of SBC-3/OPN cells was not altered. in contrast, pro-apoptotic protein, bax, was not altered in both SBC-3/OPN and SBC-3/NEO cells, thus bcl-2/bax ratio was decreased in SBC-3/NEO but not altered in SBC-3/OPN cells. Activation of caspase-3 and caspase-9 was increased in SBC-3/NEO cells, but not in SBC-3/OPN cells. Our results suggest that OPN enhances chemo-resistance of cisplatin in SBC-3 cells by suppressing bcl-2 protein down-regulation, thereby blocking the caspase-9- and caspase-3-dependent cell apoptosis. (C) 2009 Elsevier Ireland Ltd. All rights reserved.